DESCRIPTION: (Applicant's Abstract) There is growing evidence supporting the hypothesis that polymorphisms in the genes encoding critical HIV entry cofactors (chemokine receptors) and their ligands, as well the major histocompatibility (MHC) proteins strongly influence HIV-1 transmission and AIDS pathogenesis. For example, we have demonstrated recently that polymorphisms in the regulatory regions of CCR5, the coding regions of CCR2B, and the chemokine SDF are associated with altered rates of HIV-1 disease progression (Nature Medicine, 1998). However, there remain many unanswered questions about the differential effects of these polymorphisms among racial groups and the mechanisms by which they influence HIV pathogenesis. Furthermore, almost all studies completed to date have focuses on homosexual Caucasians, and consequently there is little data about the genetic basis of HIV susceptibility in African-Americans. In this Collaborative Study of the Mechanism of AIDS Pathogenesis we will: (1) identify CCR5 haplotypes that influence HIV transmission and disease progression; (2) determine whether CCR5 haplotypes produce race-specific effects on HIV susceptibility; (3) explore the impact of polymorphisms in CC chemokines and MHC genes on HIV pathogenesis; and (4) elucidate the mechanisms by which chemokine system gene variants mediate their HIV disease-modifying effects. There are two compelling strengths of this proposal. First, to address directly the importance of the genetic components of HIV disease, we will take advantage of the largest cohort of HIV-1 seropositive individuals (1,158 patients) followed at a single U.S. medical center. Several unique epidemiological features, including the large number of Caucasians and African-Americans in this cohort, provide us with the power to detect race-specific effects of genetic polymorphisms. Second, to fully comprehend the impact of individual genetic variants, all of the proposed studies will be interpreted in an evolutionary context. For example, reconstructing the phylogeny of chemokine system gene variants provides the biological framework for designing studies of disease association and more importantly, for developing population-specific anti-HIV-1 strategies. In preliminary studies, we have discovered that (a) the amount and complexity of sequence variation at CCR5 is considerably more than currently appreciated; (b) the disease-accelerating or disease-retarding effects of some CCR5 haplotypes can be race-specific; (c) there is genetic variability in the genes encoding the HIV suppressive CC chemokines; and (d) the interaction between trans-acting factors and cis-acting polymorphic regulatory sites can involve differential nuclear factor binding. These data document our ability to complete successfully the proposed specific aims. Thus, this proposal seeks funds to support a burgeoning collaborative study to explore the genetic mechanisms underlying HIV susceptibility by integrating the unique skills/resources of three different research teams, namely coreceptors (UTHSCSA)-evolutionary biology (U. of Utah)-epidemiology/virology/statistics (WHMC). Significance: These studies have the potential to provide insights into the complex interplay between polymorphisms in chemokine genes and MHC gene variants in HIV-1 pathogenesis, which will in turn will determine the mechanisms that mediate the disease-modifying effects of chemokine and HIV-1 co-receptor variants. Approach: The investigators hypothesize that the genetic constitution of an individual influences susceptibility to HIV-1 infections as well as disease progression. The investigators specifically propose to: 1) identify CCR5 haplotypes that influence HIV transmission and disease progression; 2) determine the CCR5 haplotypes responsible for differential racial susceptibility to HIV-1 infection; 3) determine the influence of genetic variability in CC chemokines and MHC genes on HIV pathogenesis; and 4) determine the mechanisms by which chemokine system gene variants mediate their HIV disease-modifying effects. To facilitate addressing these questions, the investigators propose to establish a collaborative study, combining the unique skills and resources of three different research groups, namely chemokine/co-receptors (UTHSCSA), evolutionary biology/population genetics (UTAH), and epidemiology/virology/statistics (WHMC).